This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Rodriguez, G. C. Articles by Cline, J.M. PubMed PubMed Citation Articles by Rodriguez, G. C. Articles by Cline, J.M. Related Collections Clinical Intervention Clinical Intervention: Biomarkers Preclinical Intervention Preclinical Intervention: In Vivo (Animals): Drugs, Nutritional Interventions, Mechanisms

Progestin Treatment Induces Apoptosis and Modulates Transforming Growth Factor-β in the Uterine Endometrium

Divisions of ¹ Gynecologic Oncology and ² Pathology, Evanston Northwestern Healthcare, Feinberg School of Medicine, Northwestern University; ³ Center on Outcomes, Research and Education, Evanston Northwestern Healthcare, Evanston, Illinois; ⁴ Gynecologic Disease Center and the U.S. Military Cancer Institute, Walter Reed Army Medical Center, Washington, District of Columbia; and ⁵ Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Requests for reprints: Gustavo C. Rodriguez, Division of Gynecologic Oncology, Evanston Northwestern Healthcare, Feinberg School of Medicine, Northwestern University, Suite 1507, Walgreen Building, 2650 Ridge Avenue, Evanston, IL 60201. Phone: 847-570-2164; Fax: 847-733-5398. E-mail: grodriguez{at}enh.org

Background: Epidemiologic, animal, and human data suggest that progestins are potent endometrial cancer preventive agents. In the ovarian surface epithelium, progestins have been hypothesized to confer a cancer preventive effect via apoptosis and modulation of transforming growth factor-β (TGF-β). Given that the ovarian epithelium and endometrium share a common embryologic origin and similar reproductive and hormonal risk factors for malignancy, we tested the hypothesis that progestins confer biological effects in the endometrium similar to those in the ovary.

Methods: Postmenopausal female macaques (n = 78) were randomized into four groups to receive a diet for 36 months containing no hormone versus conjugated equine estrogen (CEE), medroxyprogesterone acetate (MPA), or CEE + MPA. The endometrium was then examined immunohistochemically for treatment-specific changes using antibodies to activated caspase-3 (for apoptosis), Ki-67 (proliferation), and the TGF-β1, TGF-β2, and TGF-β3 isoforms.

Results: Percentages of caspase-positive endometrial glandular cells were 3- to 5-fold higher in CEE + MPA–treated animals compared with all others (P < 0.05). Caspase-expressing cells were six times more numerous in the endometrial stroma of animals treated with MPA alone relative to other groups (P < 0.0001). Induction of endometrial glandular cell apoptosis in the CEE + MPA–treated group was associated with a dramatic increase in expression of TGF-β2 and TGF-β3 in the stromal compartment of the endometrium (P < 0.0001).

Conclusion: Progestin treatment activates chemopreventive biological effects in the endometrium that are similar to those in the ovarian surface epithelium. These data may facilitate identification of a chemopreventive approach that dramatically lessens the risk of both uterine and ovarian cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(3):578–84)